Hepatocyte growth factor (HGF) receptor, also known as c-Met, is a tyrosine kinase receptor. It is a mature receptor formed by linking α and β subunits which are derived from a single-chain protein precursor by disulfide bonds.
c-Met is a membrane receptor, which is essential to embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of c-Met receptor. c-Met is usually expressed in epithelial cells, and the expression of HGF is limited to mesenchymal cells. After excitation by HGF, c-Met can induce some biological responses, these biological responses act synergistically, thereby leading to cell survival and proliferation, cell migration and invasion to other tissues, and blocking apoptosis.
Abnormal activation of c-Met is related to a poor prognosis of cancer. In the face of abnormal activation, c-Met can lead to tumor growth and formation of new blood vessels (angiogenesis, which can provide nutrients to the tumor) which will help the cancer spread to other organs (metastasis). In many types of human malignancies, such as bladder cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, breast cancer, squamous cell carcinoma, and brain cancer, there exists c-Met overexpression or disorder (WO2007/126799).
c-Met abnormality is found in many types of tumors, such as hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), stomach cancer, and colon cancer, etc. c-Met abnormality may manifest as increased expression of c-Met, gene amplification, gene mutation or increased expression of HGF. In these abnormal circumstances, c-Met may be activated in an abnormal state, which contributes to carcinogenesis and poor prognosis. Because of these properties, c-Met is an important target for the treatment of many cancers. In the pharmaceutical industry, drugs that target c-Met can be divided into three categories: c-Met specific drugs, multiple target (including c-Met) selective drugs, and antibody drugs.
Inhibition of c-Met signal pathway is an important therapeutic strategy for cancer. Many small molecule compounds were found to effectively block the HGF/c-Met signal transduction pathway, but so far there is no small molecule inhibitor of c-Met tyrosine kinase on the market.
There is no c-Met specific drug approved by FDA. The compounds in clinical trials intended as C-Met specific drugs include SGX-523, JNJ38877605 (Johnson & Johnson), AMG-208, and INCB28060 (Novartis/InCyte). SNG-523 and JNJ38877605 were discontinued in clinical trials due to renal toxicity. AMG-208 and INCB28060 are currently in clinical phase-I trial.